Nearly 3% of the population in the United States has been diagnosed with some form of epilepsy at an estimated annual cost of >$12 billion. A major goal of translational research in the field of epilepsy is to develop therapies that prevent epilepsy development in high-risk individuals, such as stroke or brain trauma patients. Novel drugs that selectively inhibit cyclooxygenase-2 (COX-2) represent a key advancement in this important class of drugs. Their improved tolerability has allowed management of chronic inflammatory diseases like arthritis and proliferative disorders including cancer. Recent results from several laboratories including our's (Hewett) now suggest that selective inhibitors with superior activity against neuronal COX-2 can be developed for the prevention of epilepsy. We have developed three novel chemotypes (pyrazolines, hydrazones and acetyl sulfides) with potent and selective COX-2 inhibitory activity. Preliminary work with these compounds has demonstrated a good safety profile in animals and in neuronal cells in culture. The Specific Aims of this proposal are: Short term (12 months). Employing the mini library of COX- 2 inhibitors created around three new chemotypes, we will evaluate the inhibition of COX-2 in an animal model of epileptogenesis. Based on these results, we will prepare additional novel analogs within these chemotypes for further evaluation. Using our biological assay and tools of molecular modeling, we will establish a SAR pattern of activity with our novel series of compounds. Intermediate term. Identify a candidate for Investigational New Drug (IND) application leading to Phase 1 studies for the treatment of epilepsy. Based on our results, we will identify clinical collaborators at the National Institutes of Health (NIH) and other institutions to develop a clinical testing plan. We will contract with a GMP manufacturer to produce material for advanced pre-clinical studies and the IND. Long term. A candidate that successfully completes Phase 1 will be further developed. The later studies for Phase 2 and Phase 3 evaluations can be earned out internally or with a commercial partner, depending on the results of the early studies and the needs of the company.